Imidazole derivatives and processes for the preparation thereof

ABSTRACT

Novel imidazole derivatives of formula(I) inhibit effectively the action of angiotensin II and have a superior antihypertensive activity: ##STR1## wherein: A is a straight, branched or cyclic C 1  -C 6  alkyl group, or OR 1  wherein R 1  is a hydrogen, or a straight, branched or cyclic C 1  -C 6  alkyl radical; B is a halogen, CF 3  or CF 2  CF 3  ; X is N or N-oxide; Y is --CH 2  --, --CH(OR 1 )-- wherein R 1  is the same as defined above, or --C(═O)--; n is 0 or an integer of 1 to 4; Z is a halogen, --OH, --OR 1 , --NR 1  R 2 , --N(═O)R 3  R 4 , --C(═O)R 1 , --C(═O)OR 1 , --CH(OR 1 ) 2  or --C(═O)N 1  N 2  wherein R 1  is the same as defined above, R 2  is, independently of R 1 , a hydrogen, or a straight, branched or cyclic C 1  -C 6  alkyl radical, and R 3  and R 4  are independently a straight, branched or cyclic C 1  -C 6  alkyl radical; and D is a hydrogen, or a straight, branched or cyclic C 1  -C 6  alkyl radical.

FIELD OF THE INVENTION

The present invention relates to novel imidazole derivatives, processesfor preparing them and pharmaceutical compositions containing same asactive ingredients.

BACKGROUND OF THE INVENTION

Various imidazole derivatives, which can inhibit the action ofangiotensin II, have been used for the treatment of hypertension causedby angiotensin II. Angiotensin II is produced by an angiotensinconverting enzyme from angiotensin I, which is formed fromangiotensinogen by the action of renin. Angiotensin II, which is apotent vasoconstrictor interacting with specific receptors on cellmembrane, has been reported to cause hypertension in mammals includinghuman beings.

Many studies have been made to search for an antagonist which inhibitsthe action of angiotensin II on the receptors of its target cell inorder to suppress the elevation of blood pressure. As a result, manyimidazole derivatives have been developed (see A. T. Chiu et al., Eur.J. Pharm., 157, 13(1981); P. C. Wong et al., J. Pharmacol. Exp. Ther.,247, 1(1988); and P. C. Wong et al., Hypertension, 13, 489(1989)).

As a representative of these compounds, for example, D. J. Carini et al.reported in J. Med. Chem., 34, 2525(1990) imidazole derivatives of thefollowing formula (A): ##STR2##

Despite these discoveries, however, needs have continued to exist forthe development of more effective agents which possess enhancedantagonistic property against angiotensin II.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide novelimidazole derivatives and pharmacologically acceptable salts thereofhaving an enhanced ability to suppress the activity of angiotensin II.

Another object of the present invention is to provide novel processesfor preparing the inventive derivatives.

A further object of the present invention is to provide pharmaceuticalcompositions containing same as active ingredients.

In accordance with the present invention, there is provided novelimidazole compounds of formula (I) and pharmacologically acceptablesalts thereof: ##STR3## wherein: A is a straight, branched or cyclic C₁-C₆ alkyl group, or OR₁ wherein R₁ is a hydrogen, or a straight,branched or cyclic C₁ -C₆ alkyl radical;

B is a halogen, CF₃ or CF₂ CF₃ ;

X is N or N-oxide;

Y is --CH₂ --, --CH(OR₁)-- wherein R₁ is the same as defined above, or--C(═O)--;

n is 0 or an integer of 1 to 4;

Z is a halogen, --OH, --OR₁, --NR₁ NR₂, --N(═O)R₃ R₄, --C(═O)R₁,--C(═O)OR₁, --CH(OR₁)₂ or --C(═O)NR₁ R₂ wherein R₁ is the same asdefined above, R₂ is, independently of R₁, a hydrogen, or a straight,branched or cyclic C₁ -C₆ alkyl radical, and R₃ and R₄ are independentlya straight, branched or cyclic C₁ -C₆ alkyl radical; and

D is a hydrogen, or a straight, branched or cyclic C₁ -C₆ alkyl radical.

DETAILED DESCRIPTION OF THE INVENTION

Among the compounds of formula (I) of the present invention, preferredare those wherein:

A is a C₃ -C₅ alkyl group;

B is Cl;

X is N or N-oxide;

Y is --CH(OH)-- or --C(═O)--;

n is 0 or 1;

Z is --OH, --NR₁ R₂, --N(═O)R₃ R₄, --C(═O)R₁ or --CH(OR₁)₂ wherein R₁and R₂ are independently a hydrogen or a C₁ -C₃ alkyl radical, and R₃and R₄ are independently a C₁ -C₃ alkyl radical; and

D is a hydrogen, or a straight, branched or cyclic C₁ -C₄ alkyl radical.

Exemplary compounds of formula (I) of the present invention are:

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(dimethoxymethyl)-1-oxypyridin-2-yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-formyl-1-oxypyridin-2-yl)methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-hydroxymethyl-1-oxypyridin-2-yl)methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(dimethoxymethyl)pyridin-2-yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-formylpyridin-2-yl)methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(diethylamino)methyl-1-oxypyridin-2-yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-((diethyl)(oxy)amino)methyl-1-oxypyridin-2-yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-((diethylamino)methyl)pyridin-2-yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-[((diethyl)(oxy)amino)methyl]pyridin-2-yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-bromo-1-oxypyridin-2-yl)methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(1-hydroxyethyl)-1-oxypyridin-2-yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-acetyl-1-oxypyridin-2-yl)methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-methoxycarbonyl-1-oxypyridin-2-yl)methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)-1-oxypyridin-2-yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(5-formyl-1-oxypyridin-2-yl)methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)pyridin-2-yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(diethylamino)methyl-1-oxypyridin-2-yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-((diethyl)(oxy)amino)methyl-1-oxypyridin-2yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-((diethylamino)methyl)pyridin-2-yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo1-4-yl}{5-[((diethyl)(oxy)amino)methyl]pyridin-2-yl}methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(diethylamino)carbonyl-1-oxypyridin-2-yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(hydroxyimino)methyl-1-oxypyridin-2-yl]methanone;

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)-6-methyl-1-oxypyridin-2-yl]methanone;and

{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(5-formyl-6-methyl-1-oxypyridin-2-yl)methanone.

The imidazole derivatives of formula (I) of the present invention may beprepared in accordance with the procedure described below:

Pyridine or pyridine N-oxide compound of formula (II) is reacted with analkyl lithium to produce a lithium compound of formula (II'), which isthen reacted with a compound of formula (III) to give a compound offormula (IV): ##STR4## wherein: J is Br, Cl or H;

K is --(CH₂)_(n) CH(OR₁)₂ or --(CH₂)_(n) NR₁ R₂ wherein R₁ and R₂ arethe same as defined previously;

P₁ is a tetrazole protecting group such as 1-ethoxyethyl; and

A, B, D, X and n are the same as defined previously.

Then, the compound of formula (IV) is oxidized with an oxidizing agentsuch as chromium trioxide, pyridium dichromate, dimethylsulfoxide-oxalylchloride or manganese dioxide to give a compound of formula (V):##STR5## wherein A, B, D, K, P₁ and X are the same as definedpreviously.

The compound of formula (IV) or (V) is then deprotected by hydrolysis inthe presence of an acid such as hydrochloric acid, sulfuric acid ortoluensulfonic acid to give a compound of formula (VI) or (VII),respectively. Said reaction is carried out in a solvent such as water,water-tetrahydrofuran and alcohol. ##STR6## wherein A, B, D, K and X arethe same as defined previously.

The compound of formula (VI) or (VII) may be converted into theimidazole derivatives of formula (I) of the present invention.

The present invention also provides pharmacologically acceptable salts,preferably, sodium or potassium salts of the compounds of formula (I)which may be prepared by a conventional method.

The novel imidazole derivatives of the present invention andpharmacologically acceptable salts thereof have an antihypertensiveactivity due to their antagonistic action against angiotensin II; and,therefore, may be useful for the treatment of acute or chronic cardiacdeficiencies and various renal disorders as well as hypertension. Thecompounds of the present invention may be also useful for the treatmentof migraine, Raynaud's disease and various ocular diseases caused byelevated intraocular pressure and for the prevention of the progress ofatherosclerosis.

The compounds may be used alone or together with other antihypertensiveagents such as a diuretic, an angiotensin converting enzyme inhibitor, acalcium-channel blocker, a potassium-channel blocker and the like.

Accordingly, the present invention also provides pharmaceuticalcompositions containing the compounds of formula (I) andpharmacologically acceptable salts thereof as active ingredients, andpharmaceutically acceptable carriers.

The pharmaceutical compositions of the present invention may beadministered orally or parenterally. These compositions may be in a unitdosage form of tablets, capsules or powder. The pharmaceuticalcomposition in a unit dosage may comprise about 0.1 to 1000 mg,preferably 1 to 500 mg of the active ingredient; and may be administered4 times or less, preferably once or twice per day for an adult dependingon the age and body weight of the patient, the kind and severity of theillness, and so on. The compositions of the present invention maycomprise conventional adjuvants such as a filler, binder lubricant andflavoring agent. The formulation may be carried out in accordance with aconventional method.

The following Examples are intended to illustrate the present inventionmore specifically, without limiting the scope of the invention. Thepercentages as used in the Examples are by v/v, unless otherwisespecified.

EXAMPLE 1 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(dimethoxymethyl)-1-oxypyridin-2-yl]methanone

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(dimethoxymethyl)pyridin-2-yl]methanol

1.71 g (7.36 mmole) of 2-bromo-6-(dimethoxymethyl)pyridin was dissolvedin 15 ml of tetrahydrofuran and the solution was cooled to -78° C.Thereto was added 2.65 ml (6.62 mmole) of 2.5M n-butyl lithium solutionin hexane and the resultant was stirred for 30 minutes at -78° C. 1.811g (368 mmole) of2-butyl-4-chloro-1-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazol-5-carboxyaldehydein 20 ml of tetrahydrofuran was added to the above reaction mixture at-78° C. and stirred for 2 hours at the same temperature. 20 ml of waterwas added thereto and the resultant was extracted with 50 ml of ethylacetate. The organic layer was washed with 10 ml of water, dried overanhydrous Na₂ S₄, concentrated under reduced pressure and purified withsilica gel column chromatography to obtain 1.5 g of the title compound(yield 63%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(dimethoxymethyl)pyridin-2-yl]methanone

399.7 mg (0.619 mmole) of the compound obtained in step 1 was dissolvedin 7 ml of methylene chloride and to the resulting solution was added890 mg (10.2 mmole) of manganese dioxide. The mixture was stirred for 5hours at room temperature and the resultant was removed from the solventand purified with silica gel column chromatography to obtain 370 mg ofthe title compound (yield 93%).

Step 3: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(dimethoxymethyl)-1-oxypyridin-2-yl]methanone

554 mg (0.86 mmole) of tie compound obtained in step 2 was dissolved in10 ml of methylene chloride and to the resulting solution was added 445mg (1.29 mmole) of 3-chloroperoxybenzoic acid (50%). The mixture wasstirred for 15 hours at room temperature and washed with 10 ml ofaqueous sodium bicarbonate solution and 7 ml of water. The organic layerwas dried over anhydrous Na₂ SO₄, concentrated under reduced pressureand purified with silica gel column chromatography to obtain 186.8 mg ofthe title compound (yield 33%).

Step 4: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(dimethoxymethyl)-1-oxypyridin-2-yl]methanone

To 30.2 mg (0.046 mmole) of the compound obtained in step 3 was added0.5 ml of 3% hydrogen chloride/methanol solution and the resultingsolution was stirred for 5 minutes at room temperature. After beingadded with a small amount of sodium bicarbonate, the solution wasconcentrated under reduced pressure and the residue was purified withsilica gel column chromatography to obtain 22.5 mg of the title compound(yield 83%).

¹ H NMR(CD₃ OD) δ0.89(t, 3H), 1.33(m, 2H), 1.60(m, 2H), 2.70(t, 2H),3.44(s, 6H), 5.73(s, 2H), 5.81(s, 1H), 7.15(s, 4H), 7.50-7.90(m, 7H)

EXAMPLE 2 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-formyl-1-oxypyridin-2-yl)methanone

186.8 mg (0.28 mmole) of the compound obtained in step 3 of Example 1was dissolved in 3 ml of tetrahydrofuran and to the resulting solutionwas added 3 ml of aqueous 4N HCl solution. The resultant was stirred for15 hours at room temperature, neutralized with aqueous 4N NaOH solution,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 144 mg of the title compound (yield 95%).

¹ H NMR(CDCl₃) δ0.98(t, 3H), 1.50(m, 2H), 1.87(m, 2H), 1.90(t, 2H),5.54(s, 2H), 7.15(q, 4H), 7.40-7.58(m, 5H), 7.95(t, 1H), 8.10(d, 1H)

EXAMPLE 3 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-hydroxymethyl-1-oxypyridin-2-yl)methanone

85.8 mg (0.158 mmole) of the compound obtained in Example 2 wasdissolved in 4 ml of tetrahydrofuran and the solution was cooled to -78°C. To the resulting solution was added 0.38 ml (0.1896 mmole) of 0.5Mlithium tris[(3-ethyl-3-pentyl)oxy]aluminohydride solution intetrahydrofuran and the resultant was stirred for 1.5 hours at -78° C.Then, 0.3 ml (0.3 mmole) of aqueous 1N HCl solution was added theretoand the resulting mixture was concentrated under reduced pressure andpurified with silica gel column chromatography to obtain 62.7 mg of thetitle compound (yield 72.8%).

¹ H NMR(CD₃ OD) δ0.90(t, 3H), 1.34(m, 2H), 1.60(m, 2H), 2.74(t, 2H),4.80(s, 2H), 5.76(s, 2H), 7.14(s, 4H), 7.48-7.90(m, 7H)

EXAMPLE 4 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(dimethoxymethyl)pyridin-2-yl]methanol

To 50 mg (0.077 mmole) of the compound obtained in step 1 of Example 1was added 1 ml of 3% hydrogen chloride/methanol solution and theresulting solution was stirred for 10 minutes at room temperature. Afterbeing added with a small amount of Na₂ CO₃, the resultant wasconcentrated under reduced pressure and purified with silica gel columnchromatography to obtain 37.7 mg of the title compound (yield 85%).

¹ H NMR(CD₃ OD) δ0.85(t, 3H), 1.30(m, 2H), 1.50(m, 2H), 2.45(t, 3H),3.22(s, 6H), 5.23(s, 1H), 5.25(q, 2H), 6.04(s, 1H), 6.73(d, 2H), 6.99(d,2H), 7.30-7.73(m, 7H)

EXAMPLE 5 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-formylpyridin-2-yl)methanol

150 mg (0.23 mmole) of the compound obtained in step 1 of Example 1 wasdissolved in 3 ml of tetrahydrofuran and to the resulting solution wasadded 2 ml of aqueous 4N HCl solution. The resultant was stirred for 15hours at room temperature, neutralized with aqueous 4N NaOH solution,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 101 mg of the title compound (yield 83%).

¹ H NMR(DMSO-d₆) δ0.80(t, 3H), 1.25(m, 2H), 1.48(m, 2H), 2.40(t, 2H),5.23(s, 2H), 5.99(s, 1H), 6.60(d, 2H), 6.90(d, 2H), 7.10-7.90(m, 7H), 59.80(s, 1H)

EXAMPLE 6 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(dimethoxymethyl)pyridin-2-yl]methanone

To 38 mg (0.059 mmole) of the compound obtained in step 2 of Example 1was added 1 ml of 3% hydrogen chloride/methanol solution and theresulting solution was stirred for 10 minutes at room temperature. Afterbeing added with a small amount of Na₂ CO₃, the resultant wasconcentrated under reduced pressure and purified with silica gel columnchromatography to obtain 26.6 mg of the title compound (yield 78.9%).

¹ H NMR(CD₃ OD) δ0.90(t, 3H), 1.35(m, 2H), 1.60(m, 2H), 2.69(t, 2H),3.39(s, 6H), 5.38(s, 1H), 5.58(s, 2H), 7.09(q, 4H), 7.35-7.60(m, 4H),7.70(d, 1H), 7.79(d, 1H), 8.01(t, 1H)

EXAMPLE 7 Preparation of{2-butyl-5-chloro-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-formylpyridin-2-yl)methanone

186 mg (0.289 mmole) of the compound obtained in step 2 of Example 1 wasdissolved in 3 ml of tetrahydrofuran and to the resulting solution wasadded 2 ml of aqueous 4N HCl solution. The resultant was stirred for 15hours at room temperature, neutralized with aqueous 4N NaOH solution,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 108 mg of the title compound (yield 71%).

¹ H NMR(DMSO-d₆) δ0.84(t, 3H), 1.30(m, 2H), 1.58(m, 2H), 2.70(t, 2H),5.57(s, 2H), 7.00(d, 2H), 7.10(d, 2H), 7.39-7.60(m, 4H), 8.02(d, 1H),8.13(d, 1H), 8.27(t, 1H), 10.00(s, 1H)

EXAMPLE 8 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(hydroxymethyl)pyridin-2-yl]methanone

The same procedure as in Example 3 was repeated using 56.5 mg (0.107mmole) of the compound obtained in Example 7 to obtain 26.7 mg of thetitle compound (yield 47%).

¹ H NMR(CD₃ OD) δ0.84(t, 3H), 1.26(m, 2H), 1.54(m, 2H), 2.54(t, 2H),4.80(s, 2H), 5.32(s, 2H), 6.86(d, 2H), 7.01(d, 2H), 7.30-7.55(m, 4H),7.50(d, 1H), 7.79(t, 1H), 7.99(t, 1H)

EXAMPLE 9 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(diethylamino)methyl-1-oxypyridin-2-yl]methanol

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(diethylamino)methyl-1-oxypyridin-2-yl]methanol

352 mg (1.36 mmole) of 2-bromo-6-(diethylamino)methyl-1-oxypyridine wasdissolved in 5 ml of tetrahydrofuran and the solution was cooled to -78°C. Thereto was added 0.48 ml (1.206 mmole) of 2.5M n-butyl lithiumsolution in hexane and the resultant was stirred for 20 minutes at -78°C. 331.5 mg (0.67 mmole) of2-butyl-4-chloro-1-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazol-5-carboxyaldehydein 5 ml of tetrahydrofuran was added to the above reaction mixture at-78° C. and the mixture was stirred for 3 hours at the same temperature.7 ml of aqueous sodium bicarbonate solution was added thereto and theresultant was extracted with 20 ml of ethyl acetate. The organic layerwas washed with 10 ml of water, dried over anhydrous Na₂ SO₄,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 289 mg of the title compound (yield 64%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(diethylamino)methyl-1-oxypyridin-2-yl]methanol

56.1 mg (0.083 mmole) of the compound obtained in step 1 was dissolvedin 1 ml of tetrahydrofuran and to the resulting solution was added 0.5ml of aqueous 1N HCl solution. The resultant was stirred for 2.5 hoursat room temperature, neutralized with aqueous 1N NaOH solution,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 46 mg of the title compound (yield 92%).

¹ H NMR(CD₃ OD) δ0.86(t, 3H), 1.28(t, 6H), 1.30(m, 2H), 1.54(m, 2H),2.52(t, 2H), 3.13(q, 4H), 4.34(s, 2H), 5.34(q, 2H), 6.14(s, 1H), 6.75(d,2H), 7.04(d, 2H), 7.30-7.60(m, 6H), 8.00(d, 1H)

EXAMPLE 10 Preparation of{2-butyl-5-chloro-3-[-2'-(1H,-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-diethylamino)methyl-1-oxypyridin-2-yl]methanone

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(diethylamino)methyl-1-oxypyridin-2-yl]methanone

232 mg (0.34 mmole) of the compound obtained in step 1 of Example 9 wasdissolved in 6 ml of methylene chloride and to the resulting solutionwas added 296 mg (3.4 mmole) of manganese dioxide. The resultant wasstirred for 1.5 hours at room temperature and purified with silica gelcolumn chromatography to obtain 195 mg of the title compound (yield85.6%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo1-4-yl}[6-(diethylamino)methyl-1-oxypyridin-2-yl]methanone

86 mg (0.128 mmole) of the compound obtained in step 1 was dissolved in1 ml of tetrahydrofuran and to the resulting solution was added 1 ml ofaqueous 1N HCl solution. The resultant was stirred for 4 hours at roomtemperature, neutralized with aqueous 1N NaOH solution, concentratedunder reduced pressure and purified with silica gel columnchromatography to obtain 71.3 mg of the title compound (yield 93%).

¹ H NMR(CD₃ OD) δ0.92(t, 3H), 1.32(t, 6H), 1.35(m, 2H), 1.60(m, 2H),2.75(t, 2H), 3.15(q, 4H), 4.44(s, 2H), 5.73(s, 2H), 7.12(m, 4H),7.40-7.90(m, 7H)

EXAMPLE 11 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-((diethyl)(oxy)amino)methyl-1-oxypyridin-2-yl]methanone

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-((diethyl)(oxy)amino)methyl-1-oxypyridin-2-yl]methanone

58.5 mg (0.087 mmole) of the compound obtained in step 1 of Example 10was dissolved in 3 ml of methylene chloride and to the resultingsolution was added 43 mg (0.12 mmole) of 3-chloroperoxybenzoic acid(50%). The resultant was stirred for 20 minutes at room temperature,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 56.6 mg of the title compound (yield 94%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-((diethyl)(oxy)amino)methyl-1-oxypyridin-2-yl]methanone

56.6 mg (0.082 mmole) of the compound obtained in step 1 was dissolvedin 1 ml of tetrahydrofuran and to the resulting solution was added 0.8ml of aqueous 1N HCl solution. The resultant was stirred for 8 hours atroom temperature, neutralized with aqueous 1N NaOH solution,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 40 mg of the title compound (yield 79%).

¹ H NMR(CD₃ OD) δ0.80(t, 3H), 1.25(m, 2H), 1.29(t, 6H), 1.49(m, 2H),2.60(t, 2H), 3.15(m, 2H), 3.35(m, 2H), 4.68(s, 2H), 5.62(s, 2H), 7.02(q,4H)t 7.30-7.59(m, 6H), 7.97(d, 1H)

EXAMPLE 12 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-((diethylamino)methyl)pyridin-2-yl]methanol

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-((diethylamino)methyl)pyridin-2-yl]methanol

474 mg (1.95 mmole) of 2-bromo-6-[(diethylamino)methyl]pyridine wasdissolved in 7 ml of tetrahydrofuran and the solution was cooled to -78°C. Thereto was added 0.65 ml (1.625 mmole) of 2.5M n-butyl lithiumsolution in hexane and the resultant was stirred for 20 minutes at -78°C. 320.5 mg (0.65 mmole) of2-butyl-4-chloro-1-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazol-5-carboxyaldehydein 10 ml of tetrahydrofuran was added to the above reaction mixture at-78° C. and the mixture was stirred while allowing the temperature torise slowly to -10° C. 7 ml of aqueous sodium bicarbonate solution wasadded thereto and the resultant was extracted with 20 ml of ethylacetate. The organic layer was washed with 10 ml of water, dried overanhydrous Na₂ SO₄, concentrated under reduced pressure and purified withsilica gel column chromatography to obtain 113.4 mg of the titlecompound (yield 26.6%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-((diethylamino)methyl)pyridin-2-yl]methanol

49.7 mg (0.076 mmole) of the compound obtained in step 1 was dissolvedin 1 ml of tetrahydrofuran and to the resulting solution was added 0.5ml of aqueous 1N HCl solution. The resultant was stirred for 8 hours atroom temperature, neutralized with aqueous 1N NaOH solution,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 34.4 mg of the title compound (yield 77%).

¹ H NMR(CD₃ OD) δ0.80(t, 3H), 1.10-1.58(m, 4H), 1.32(t, 6H), 2.38(m,2H), 3.15(m, 4H), 4.15(q, 2H), 5.10(d, 2H), 5.58(d, 2H), 6.20(s, 1H),6.35(d, 2H), 6.96(d, 2H), 7.22-7.80(m, 7H)

EXAMPLE 13 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-((diethylamino)methyl)pyridin-2-yl]methanone

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-((diethylamino)methyl)pyridin-2-yl]methanone

50 mg (0.076 mmole) of the compound obtained in step 1 of Example 12 wasdissolved in 3 ml of methylene chloride and to the resulting solutionwas added 64.5 mg (0.152 mmole) of Des-Martin reagent. The resultant wasstirred for 2 hours at room temperature and 10 ml of methylene chloridewas added additionally thereto. The reaction mixture was washed with 5ml of aqueous sodium bicarbonate solution, dried over anhydrous Na₂ SO₄,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 43.7 mg of the title compound (yield 87.8%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-((diethylamino)methyl)pyridin-2-y_(l)]methanone

21 mg (0.032 mmole) of the compound obtained in step 1 was dissolved in0.5 ml of tetrahydrofuran and to the resulting solution was added 0.3 mlof aqueous 1N HCl solution. The resultant was stirred for 5 hours atroom temperature, neutralized with aqueous 1N NaOH solution,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 16 mg of the title compound (yield 85.8%).

¹ H NMR(CD₃ OD) δ0.94(t, 3H), 1.10(t, 6H), 1.38(m, 2H), 1.74(m, 2H),2.73(t, 2H), 2.99(q, 4H), 4.10(s, 2H), 5.44(s, 2H), 6.86(d, 2H), 6.98(d,2H), 7.28-7.68(m, 4H), 7.77(t, 1H)

EXAMPLE 14 Preparation of{2-butyl1-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-[((diethyl)(oxy)amino)methyl]pyridin-2-yl]methanone

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-[((diethyl)(oxy)amino)methyl]pyridin-2-yl]methanone

43.7 mg (0.067 mmole) of the compound obtained in step 1 of Example 13was dissolved in 3 ml of methylene chloride and to the resultingsolution was added 27.75 mg (0.0804 mmole) of 3-chloroperoxybenzoic acid(50%). The resultant was stirred for 40 minutes at room temperature,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 31.4 mg of the title compound (yield 70%).

Step 2: preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-[((diethyl)(oxy)amino)methyl]pyridin-2-yl]methanone

31 mg (0.046 mmole) of the compound obtained in step 1 was dissolved in1 ml of tetrahydrofuran and to the resulting solution was added 0.5 mlof aqueous 1N HCl solution. The resultant was stirred for 7 hours atroom temperature, neutralized with aqueous 1N NaOH solution,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 21.7 mg of the title compound (yield 78.8%).

¹ H NMR(CD₃ OD) δ0.90(t, 3H), 1.31(t, 6H), 1.38(m, 2H), 1.52(m, 2H),2.74(t, 2H), 3.28(q, 4H), 4.49(s, 2H), 5.58(s, 2H), 6.98(d, 2H), 7.08(d,2H), 7.34-7.54(m, 4H), 7.82-7.92(m, 2H), 8.05(t, 1H)

EXAMPLE 15 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-bromo-1-oxypyridin-2-yl)methanone.

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-bromo-1-oxypyridin-2-yl)methanol

228 mg (0.9 mmole) of 2,6-dibromopyridin-1-oxide was dissolved in 5 mlof tetrahydrofuran and the solution was cooled to -78° C. Thereto wasadded 0.32 ml (0.8 mmole) of 2.5M n-butyl lithium solution in hexane andthe resultant was stirred for 30 minutes at -78° C. 90.7 mg (0.184mmole) of2-butyl-4-chloro-1-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazol-5-carboxyaldehydein 3 ml of tetrahydrofuran was added to the above reaction mixture at-78° C. and the mixture was stirred for 2 hours at the same temperature.10 ml of water was added thereto and the resultant was extracted with 15ml of ethyl acetate. The organic layer was washed with 5 ml of water,dried over anhydrous Na₂ SO₄, concentrated under reduced pressure andpurified with silica gel column chromatography to obtain 83.8 mg of thetitle compound (yield 70%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-bromo-1-oxypyridin-2-yl)methanone

74.3 mg (0.11 mmole) of the compound obtained in step 1 was dissolved in3 ml of methylene chloride and to the resulting solution was added 96 mg(1.1 mmole) of manganese dioxide. The resultant was stirred for 1.5hours at room temperature and purified with silica gel columnchromatography to obtain 68 mg of the title compound (yield 93%).

Step 3: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-bromo-1-oxypyridin-2-yl)methanone

68 mg (0.1 mmole) of the compound obtained in step 2 was dissolved in 1ml of tetrahydrofuran and to the resulting solution was added 0.5 ml ofaqueous 1N HCl solution. The resultant was stirred for 4 hours at roomtemperature, neutralized with aqueous 1N NaOH solution, concentratedunder reduced pressure and purified with silica gel columnchromatography to obtain 52.7 mg of the title compound (yield 89%).

¹ H NMR(CD₃ OD) δ0.87(t, 3H), 1.32(m, 2H), 1.59(m, 2H), 2.70(t, 2H),5.76(s, 2H), 7.17(s, 4H), 7.50-7.70(m, 2H), 8.05(m, 1H)

EXAMPLE 16 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-bromo-1-oxypyridin-2-yl)methanone

71.2 mg (0.107 mmole) of the compound obtained in step of Example 15 wasdissolved in 1 ml of tetrahydrofuran and to the resulting solution wasadded 0.5 ml of aqueous 1N HCl solution. The resultant was stirred for15 hours at room temperature, neutralized with aqueous 1N NaOH solution,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 60.8 mg of the title compound (yield 95.6%).

¹ H NMR(CD₃ OD) δ0.85(t, 3H), 1.32(m, 2H), 1.53(m, 2H), 2.52(t, 2H),5.33(q, 2H), 6.10(s, 1H), 6.75(d, 2H), 7.02(d, 2H), 7.20(t, 1H),7.44-7.77(m, 5H), 7.90(d, 1H)

EXAMPLE 17 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-bromopyridin-2-yl)methanone

The same procedures as in steps 1 to 3 of Example 15 were repeated using260 mg (1.10 mmole) of 2,6-dibromopyridine instead of2,6-dibromopyridine-1-oxide, and 180 mg (0.365 mmole) of2-butyl-4-chloro-1-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazol-5-carboxyaldehydein step 1 of Example 15 to obtain 124 mg of the title compound (yield59%).

¹ H NMR(CD₃ OD) δ0.90(t, 3H), 1.35(m, 2H), 1.61(m, 2H), 2.72(t, 2H),5.57(s, 1H), 7.10(s, 4H), 7.50-7.90(m, 7H)

EXAMPLE 18 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-bromopyridin-2-yl)methanol

The same procedure as in Example 16 was repeated using 43 mg (0.066mmole) of the compound obtained in Example 17 to obtain 35.6 mg of thetitle compound (yield 93%).

¹ H NMR(CD₃ OD) δ0.84(t, 3H), 1.30(m, 2H), 1.50(m, 2H), 2.44(t, 2H),5.25(q, 2H), 5.97(s, 1H), 6.64(d, 2H), 6.98(d, 2H), 7.20(d, 1H),7.40-7.65 (m, 6H)

EXAMPLE 19 Preparation of{2-butyl-5-chloro-3-[2'-(1H-tetrazol-5-yl1)biphenyl-4-yl)methyl]-3H-imidazol-4-y1}(6-(1-hydroxyethyl)-1-oxypyridin-2-yl)methanone

41.5 mg (0.076 mmole) of the compound obtained in Example 2 wasdissolved in 4 ml of tetrahydrofuran and the solution was cooled to -78°C. To the resulting solution was added 59 μl (0.177 mmole) of 3M methylmagnesium bromide solution in ethylether and the solution was stirredfor 2.5 hours at -78° C. and then allowed the temperature to rise slowlyto room temperature while stirring. 0.1 ml of water was added theretoand the resultant was concentrated under reduced pressure and purifiedwith silica gel column chromatography to obtain 25.6 mg of the titlecompound (yield 62%).

¹ H NMR(CD₃ OD) δ0.87(t, 3H), 1.30(m, 2H), 1.52(d, 3H), 1.58(m, 2H),2.70(t, 2H), 5.29(q, 1H), 5.75(s, 2H), 7.12(s, 4H), 7.42-7.88(m, 7H)

EXAMPLE 20 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-acetyl-1-oxypyridin-2-yl)methanone

25.6 mg (0.047 mmole) of the compound obtained in Example 19 wasdissolved in 2 ml of methylene chloride and to the resulting solutionwas added 24 mg (0.0564 mmole) of Des-Martin reagent. The resultant wasstirred for 1.5 hours at room temperature, concentrated under reducedpressure and purified with silica gel column chromatography to obtain10.3 mg of the title compound (yield 40.5%).

¹ H NMR(CDCl₃) δ0.95(t, 3H), 1.45(m, 2H), 1.79(m, 2H), 2.56(s, 3H),2.81(t, 2H), 5.52(s, 2H), 7.08(q, 4H), 7.40-7.60(m, 5H), 7.78(d, 2H),7.94(d, 2H)

EXAMPLE 21 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl1)biphenyl1-4-yl)methyl]-3H-imidazol-4-yl}(6-methoxycarbonyl-1-oxypyridin-2-yl)methanone

1 ml of the aqueous solution of 69 mg (0.3 mmole) of silver oxide and 36mg (0.09 mmole) of NaOH was added to 1 ml of the aqueous solution of81.6 mg (0.15 mmole) of the compound obtained in Example 2 at roomtemperature. The resulting mixture was stirred for 2 hours at roomtemperature, filtered through Celite, adjusted to pH 4 with aqueous 1NHCl solution and concentrated under reduced pressure. Thereto was added4 ml of 3% hydrogen chloride/methanol solution and the resultant wasrefluxed for 2 hours, concentrated under reduced pressure and purifiedwith silica gel column chromatography to obtain 41 mg of the titlecompound (yield 48%).

¹ H NMR(CD₃ OD) δ0.86(t, 3H), 1.30(m, 2H), 1.57(m, 2H), 2.69(t, 2H),3.94(s, 3H), 5.74(s, 2H), 7.12(s, 4H), 7.46-7.69(m, 6H), 7.90(m, 1H)

EXAMPLE 22 Preparation{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)-1-oxypyridin-2-yl]methanone

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)pyridin-2-yl]methanol

810 mg (3.49 mmole) of 2-bromo-5-(dimethoxymethyl)pyridine was dissolvedin 8 ml of tetrahydrofuran and the solution was cooled to -78° C.Thereto was added 1.40 ml (3.49 mmole) of 2.5M n-butyl lithium solutionin hexane and the resultant was stirred for 30 minutes at -78° C. 860 mg(1.74 mmole) of2-butyl-4-chloro-1-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazol-5-carboxyaldehydein 5 ml of tetrahydrofuran was added slowly to the above reactionmixture at -78° C. and the mixture was stirred for 2 hours at the sametemperature. 10 ml of water was added thereto and the resultant wasextracted with 30 ml of ethyl acetate. The organic layer was washed with10 ml of saturated NaCl solution, dried over anhydrous Na₂ SO₄,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 1.06 g of the title compound (yield 94%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)pyridin-2-yl]methanone

500 mg (0.77 mmole) of the compound obtained in step 1 was dissolved in8 ml of methylene chloride and to the resulting solution was added 73 mg(7.74 mmole) of manganese dioxide. The mixture was stirred for 5 hoursat room temperature and the resultant was removed from the solvent andpurified with silica gel column chromatography to obtain 346 mg of thetitle compound (yield 70%).

Step 3: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)-1-oxypyridin-2-yl]methanone

377 mg (0.59 mmole) of the compound obtained in step 2 was dissolved in5 ml of methylene chloride and to the resulting solution was added 303mg (0.88 mmole) of 3-chloroperoxybenzoic acid (50%). The solution wasstirred for 15 hours at room temperature and 5 ml of aqueous saturatedsodium bicarbonate solution was added thereto. The resultant wasextracted with 20 ml of ethylacetate, washed with saturated NaClsolution, dried over anhydrous Na₂ SO₄, concentrated under reducedpressure and then purified with silica gel column chromatography toobtain 256 mg of the title compound (yield 66%).

Step 4: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)-1-oxypyridin-2-yl]methanone

To 26 mg (0.039 mmole) of the compound obtained in step 3 was added 0.5ml of 3% hydrogen chloride/methanol solution and the resulting solutionwas stirred for 10 minutes at room temperature. After being added with20 mg of sodium bicarbonate, the solution was concentrated under reducedpressure and purified with silica gel column chromatography to obtain 18mg of the title compound (yield 79%).

¹ H NMR(CD₃ OD) δ0.90(t, 3H), 1.35(m, 2H), 1.60(m, 2H), 2.73(t, 2H),3.40(s, 6H), 5.58(s, 1H), 5.77(s, 2H), 7.12(d, 2H), 7.18(d, 2H),7.52-7.78(m, 6H), 8.36(s, 1H)

EXAMPLE 23 Preparation of{2-butyl1-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(5-formyl-1-oxypyridin-2-yl)methanone

The same procedure as in Example 2 was repeated using 252 mg (0.38mmole) of the compound obtained in step 3 of Example 22 to obtain 169 mgof the title compound (yield 82%).

¹ H NMR(CDCl₁) δ1.02(t, 3H), 1.54(m, 2H), 1.90(m, 2H), 2.98(t, 2H),5.54(s, 2H), 7.09(d, 2H), 7.18(d, 2H), 7.39-7.63(m, 4H), 7.99(d, 1H),8.14(dd, 1H), 8.53(s, 1H)

EXAMPLE 24 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl1)biphenyl1-4-yl)methyl1]-3H-imidazol-4-yl}(5-hydroxymethyl-1-oxypyridin-2-yl)methanol

21 mg (0.039 mmole) of the compound obtained in Example 23 was dissolvedin 1 ml of methanol and to the resulting solution was added 3 mg ofsodium borohydride and reacted for 30 minutes. Then, the resultant wasconcentrated under reduced pressure and purified with silica gel columnchromatography to obtain 19 mg of the title compound (yield 89%).

¹ H NMR(CD₃ OD) δ0.87(t, 3H), 1.32(m, 2H), 1.54(m, 2H), 2.55(t, 2H),4.56(s, 2H), 5.31(d, 1H), 5.49(d, 1H), 6.11(s, 2H), 6.95(d, 2H), 7.05(d,2H), 7.43-7.74(m, 4H), 7.91(d, 1H), 7.99(dd, 1H), 8.18(d, 1H)

EXAMPLE 25 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)pyridin-2-yl]methanol

The same procedure as in step 4 of Example 22 was repeated using 34 mg(0.053 mmole) of the compound obtained in step 1 of Example 22 to obtain28 mg of the title compound (yield 92%).

¹ H NMR(CDCl₃) δ0.80(t, 3H), 1.25(m, 2H), 1.54(m, 2H), 2.29(t, 3H),3.20(s, 3H), 3.28(s, 3H), 4.89(d, 1H), 5.12(d, 1H), 5.32(s, 1H), 5.45(s,1H), 6.02(s, 1H), 6.53(d, 2H), 6.85(d, 2H), 7.30-7.71(m, 4H), 7.80(dd,1H), 8.41(s, 1H), 8.62(d, 1H)

EXAMPLE 26 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)pyridin-2-yl]methanone

The same procedure as in Example 6 was repeated using 34 mg (0.053mmole) of the compound obtained in step 2 of Example 22 to obtain 28 mgof the title compound (yield 92%).

¹ H NMR(CD₃ OD) δ0.92(t, 3H), 1.37(m, 2H), 1.64(m, 2H), 2.73(t, 2H),3.39(s, 6H), 5.60(s, 1H), 5.61(s, 2H), 7.11(s, 4H), 7.48-7.70(m, 4H),7.78(d, 1H), 8.05(dd, 1H), 8.69(d, 1H)

EXAMPLE 27 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl1)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(5-formylpyridin-2-yl)methanone

The same procedure as in Example 7 was repeated using 485 mg (0.75mmole) of the compound obtained in step 2 of Example 22 to obtain 320 mgof the title compound (yield 81%).

¹ H NMR(CDCl₃) δ0.82(t, 3H), 1.31(m, 2H), 1.63(m, 2H), 2.60(t, 3H),5.43(s, 2H), 7.00(brs, 4H), 7.31-7.58(m, 4H), 7.78(d, 1H), 8.30(d, 1H),9.01(s, 1H), 10.19(s, 1H)

EXAMPLE 28 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl1-4-yl)methyl]-3H-imidazol-4-yl}[5-hydroxymethyl)pyridin-2-yl]methanone

The same procedure as in Example 3 was repeated using 335 mg (2.64mmole) of the compound obtained in Example 27 to obtain 189 mg of thetitle compound (yield 56%).

¹ H NMR(CD₃ OD) δ0.92(t, 3H), 1.39(m, 2H), 1.64(m, 2H), 2.75(t, 2H),4.79(s, 2H), 5.62(s, 2H), 7.11(s, 4H), 7.48-7.67(m, 4H), 7.78(d, 1H),8.01(dd, 1H), 8.66(d, 1H)

EXAMPLE 29 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(chloromethyl)pyridin-2-yl]methanone

30 mg (0.057 mmole) of the compound obtained in Example 28 was dissolvedin 1 ml of chloroform and to the resulting solution was added 4 μl (0.57mmole) of thionyl chloride. The resultant was refluxed for 1 hour,concentrated under reduced pressure to remove the solvent and purifiedwith silica gel column chromatography to obtain 28 mg of the titlecompound (yield 91%).

¹ H NMR(CD₃ OD) δ0.92(t, 3H), 1.38(m, 2H), 1.63(m, 2H), 2.7l(t, 2H),4.80(s, 2H), 5.59(s, 2H), 7.12(s, 4H), 7.50-7.69(m, 4H), 7.79(d, 1H),8.08(dd, 1H), 8.70(d, 1H)

EXAMPLE 30 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(hydroxymethyl)pyridin-2-yl]methanol

The same procedure as in Example 24 was repeated using 36 mg (0,068mmole) of the compound obtained in Example 27 to obtain 31 mg of thetitle compound (yield 86%).

¹ H NMR(CD₃ OD) δ0.85(t, 3H), 1.27(m, 2H), 1.50(m, 2H), 2.43(t, 2H),4.55(s, 2H), 5.14(d, 1H), 5.33(d, 1H), 6.07(s, 2H), 6.72(d, 2H), 6.97(d,2H), 7.50-7.76(m, 6H), 8.34(s, 1H)

EXAMPLE 31 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(diethylamino)methyl-1-oxypyridin-2-yl]methanone

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(diethylamino)methyl-1-oxypyridin-2-yl]methanol

The same procedure as in step 1 of Example 9 was repeated using 342 mg(1.32 mmole) of 2-bromo-5-(diethylamino)methyl-1-oxypyridine and 325 mg(0.66 mmole) of2-butyl-4-chloro-1-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazol-5-carboxyaldehydeto obtain 280 mg of the title compound (yield 63%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(diethylamino)methyl-1-oxypyridin-2-yl]methanone

The same procedures as in steps 1 and 2 of Example 10 were repeatedusing 100 mg (0.15 mmole) of the compound obtained in step 1 to obtain65 mg of the title compound (yield 72%).

¹ H NMR(CD₃ OD) δ0.84(t, 3H), 1.35(t, 6H), 1.38(m, 2H), 1.50(m, 2H),2.65(t, 2H), 4.36(s, 2H), 5.50(s, 2H), 6.92(d, 2H), 7.02(d, 2H),7.35-7.60(m, 4H), 7.72(d, 1H), 8.04(dd, 1H), 8.67(d, 1H)

EXAMPLE 32 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-((diethyl)(oxy)amino)methyl-1-oxypyridin-2-yl]methanone

The same procedures as in step 1 of Example 10 and steps 1 and 2 ofExample 11 were repeated using 35 mg (0.052 mmole) of the compoundobtained in step 1 of Example 31 to obtain 15 mg of the title compound(yield 46%).

¹ H NMR(CD₃ OD) δ0.82(t, 3H), 1.28(t, 6H), 1.53(m, 2H), 2.66(t, 2H),3.21(m, 4H), 4.43(s, 2H), 5.71(s, 2H), 7.12(s, 4H)r 7.26-7.63(m, 4H),7.75(d, 1H), 7.86(d, 1H), 8.58(s, 1H)

EXAMPLE 33 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-((diethylamino)methyl1)pyridin-2-yl]methanol

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-((diethylamino)methyl)pyridin-2-yl]methanol

The same procedure as in step 1 of Example 12 was repeated using 311 mg(1.36 mmole) of 2-bromo-5-[(diethylamino)methyl]pyridin to obtain 250 mgof the title compound (yield 56%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-((diethylamino)methyl)pyridin-2-yl]methanol

The same procedure as in step 2 of Example 12 was repeated using 30 mg(0.046 mmole) of the compound obtained in step 1 to obtain 24 mg of thetitle compound (yield 89%).

¹ H NMR(CD₃ OD) δ0.84(t, 3H), 1.07(t, 6H), 1.28(m, 2H), 1.58(m, 2H),2.44(t, 2H), 2.91(q, 4H), 4.28(s, 2H), 5.12(d, 1H), 5.59(d, 1H), 6.41(d,2H), 6.85(d, 2H), 7.38-7.58(m, 5H), 7.83(dd, 1H), 8.45(d, 1H)

EXAMPLE 34 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-((diethylamino)methyl)pyridin-2-y1]methanone

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-((diethylamino)methyl)pyridin-2-yl]methanone

The same procedure as in step 1 of Example 13 was repeated using 180 mg(0.27 mmole) of the compound obtained in step 1 of Example 33 to obtain153 mg of the title compound (yield 85%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-((diethylamino)methyl)pyridin-2-yl]methanone

The same procedure as in step 2 of Example 13 was repeated using 27 mg(0.041 mmole) of the compound obtained in step 1 to obtain 18 mg of thetitle compound (yield 75%).

¹ H NMR(CD₃ OD) δ0.91(t, 3H), 1.31(t, 6H), 1.36(m, 2H), 1.66(m, 2H),2.77(t, 2H), 3.15(q, 4H), 4.39(s, 2H), 5.52(s, 2H), 6.95(d, 2H), 7.08(d,2H), 7.38-7.55(m, 4H), 7.75(d, 1H), 8.12(dd, 1H), 5 8.72(d, 1H)

EXAMPLE 35 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl1-4-yl)methyl]-3H-imidazol-4-yl}[5-[((diethyl)(oxy)amino)methyl]pyridin-2-yl}methanone

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}{5-[((diethyl(oxy)amino)methyl]pyridin-2-yl}methanone

The same procedure as in step 1 of Example 14 was repeated using 59 mg(0.09 mmole) of the compound obtained in step 1 of Example 34 to obtain34 mg of the title compound (yield 56%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}{5-[((diethyl(oxy)amino)methyl]pyridin-2-yl}methanone

The same procedure as in step 2 of Example 14 was repeated using 34 mg(0.051 mmole) of the compound obtained in step 1 to obtain 22 mg of thetitle compound (yield 72%).

¹ H NMR(CD₃ OD) δ0.83(t, 3H), 1.28(m, 2H), 1.35(m, 6H), 1.57(m, 2H),2.72(t, 2H), 3.24(m, 4H), 4.47(s, 2H), 5.72(s, 2H), 7.11(s, 4H),7.47-7.73(m, 5H), 7.90(d, 1H), 8.60(s, 1H)

EXAMPLE 36 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(diethylamino)carbonyl-1-oxypyridin-2-y1]methanol

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(diethylamino)carbonyl-1-oxypyridin-2-yl]methanol

The same procedure as in step 1 of Example 9 was repeated using 127 mg(0.65 mmole) of 2-[(diethylamino)carbonyl]pyridine-1-oxide and 148 mg(0.3 mmole) of2-butyl-4-chloro-1-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazol-5-carboxyaldehydeto obtain 82.8 mg of the title compound (yield 40%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(diethylamino)carbonyl-1-oxypyridin-2-yl]methanol

The same procedure as in step 4 of Example 1 was repeated using 27.7 mg(0.04 mmole) of the compound obtained in step 1 to obtain 17.2 mg of anisomeric mixture of the title compound (yield 69%).

¹ H NMR(CD₃ OD) δ0.79(t, 3H), 1.00(m, 3H), 1.20(m, 5H), 1.45(m, 2H),2.47(m, 2H), 3.06(m, 2H), 3.49(m, 2H), 5.40(m, 2H), 6.00(s, 0.5H),6.04(s, 0.5H), 6.82(d, 1H), 7.02(d, 1H), 7.07(s, 2H), 7.50(m, 6H),7.90(m, 1H)

EXAMPLE 37 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(diethylamino)carbonyl-1-oxypyridin-2-yl]methanone

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(diethylamino)carbonyl-1-oxypyridin-2-yl]methanone

The same procedure as in step 2 of Example 1 was repeated using 50 mg(0.073 mmole) of the compound obtained in step 1 of Example 36 to obtain38.7 mg of the title compound (yield 77%).

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(diethylamino)carbonyl-1-oxypyridin-2-yl]methanone

The same procedure as in step 4 of Example 1 was repeated using 38.7 mg(0.056 mmole) of the compound obtained in step 1 to obtain 30 mg of thetitle compound (yield 87%).

¹ H NMR(CD₃ OD) δ0.83(t, 3H), 1.10(t, 3H), 1.20(t, 3H), 1.25(m, 2H),1.54(m, 2H), 2.66(t, 2H), 3.24(q, 2H), 3.52(m, 2H), 5.70(brs, 2H),7.10(brs, 4H), 7.59(m, 7H)

EXAMPLE 38 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl-}[6-(hydroxyimino)methyl-1-oxypyridin-2-y1]methanone

27 mg (0.0497 mmole) of the compound obtained in Example 2 was dissolvedin the mixture of 1 ml of methanol and 0.5 ml of water, and to theresulting solution were added 5.18 mg (0.0745 mmole) of hydroxylaminehydrogen chloride and 11.6 mg (0.141 mmole) of sodium acetate. Theresultant was stirred for 2 hours at room temperature concentrated underreduced pressure and purified with silica gel column chromatography toobtain 18.8 mg of the title compound (yield 68%).

¹ H NMR(CD₃ OD) δ0.82(t, 3H), 1.28(m, 2H), 1.52(m, 2H), 2.64(t, 2H),5.69(s, 2H), 7.10(s, 4H), 7.40-7.62(m, 6H), 8.00(d, 1H), 8.53(s, 1H)

EXAMPLE 39 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)-6-methyl-1-oxypyridin-2-yl]methanone

Step 1: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)-6-methyl-1-oxypyridin-2-yl]methanol

486 mg (2.65 mmole) of 2-methyl-3-dimethoxymethyl-1-oxypyridine wasdissolved in 9 ml of diethylether and the solution was cooled to -78° C.Thereto was added 0.97 ml (2.42 mmole) of 2.5M n-butyl lithium solutionin hexane and the resultant was stirred for 30 minutes at -78° C. 664 mg(1.346 mmole) of2-butyl-4-chloro-1-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazol-5-carboxyaldehydein 5 ml of diethylether was added to the above reaction mixture at -78°C., and the mixture was stirred for 3 hours at the same temperature andthen allowed the temperature to rise slowly to room temperature whilestirring. 10 ml of aqueous sodium bicarbonate solution was added theretoand the resultant was extracted with 30 ml of ethyl acetate. The organiclayer was washed with 10 ml of water, dried over anhydrous Na₂ SO₄,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 341 mg of the title compound including otherunseparated compounds, which was used in the next step as it is.

Step 2: Preparation of{2-butyl-5-chloro-3-[(2'-(1-(1-ethoxyethyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)-6-methyl-1-oxypyridin-2-yl]methanone.

341 mg of the compound obtained in step 1 was dissolved in 5 ml ofmethylene chloride and to the resulting solution was added 438 mg (5.04mmole) of manganese dioxide. The resultant was stirred for 3 hours atroom temperature and purified with silica gel column chromatography toobtain 143.5 mg of the title compound (yield 15.8%).

Step 3: Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)-6-methyl-1-oxypyridin-2-yl]methanone

To 33 mg (0.049 mmole) of the compound obtained in step 2 was added 1 mlof 3% hydrogen chloride/methanol solution and the resulting solution wasstirred for 5 minutes at room temperature. After being added with asmall amount of sodium bicarbonate, the solution was concentrated underreduced pressure and purified with silica gel column chromatography toobtain 24.9 mg of the title compound (yield 84%).

¹ H NMR(CD₃ OD) δ0.84(t, 3H), 1.28(m, 2H), 1.52(m, 2H), 2.49(s, 3H),2.66(t, 2H), 3.35(s, 6H), 5.56(s, 1H), 5.72(s, 2H), 7.11(brs, 4H),7.40(d, 1H), 7.44-7.68(m, 4H), 7.77(d, 2H)

EXAMPLE 40 Preparation of{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl1-4-yl)methyl]-3H-imidazol-4-yl}(5-formyl-6-methyl-1-oxypyridin-2-yl)methanone

143.5 mg (0.21 mmole) of the compound obtained in step 2 of Example 39was dissolved in 1 ml of tetrahydrofuran and to the resulting solutionwas added 1 ml of aqueous 5N HCl solution. The resultant was stirred for15 hours at room temperature, neutralized with aqueous 4N NaOH solution,concentrated under reduced pressure and purified with silica gel columnchromatography to obtain 62.8 mg of the title compound (yield 54%).

¹ H NMR(CDCl₃) δ1.00(t, 3H), 1.50(m, 2H), 1.85(m, 2H), 2.58(s, 3H),2.92(t, 2H), 5.53(brs, 2H), 7.13(q, 4H), 7.40-7.62(m, 4H), 7.94(d, 1H),8.05(dd, 1H), 10.24(s, 1H)

Activity Test

The inventive compounds were tested to measure their angiotensin IIreceptor binding capacity as follows.

1. Angiotensin II receptor binding assay

In accordance with the procedure disclosed in Chiu, A. T. et al., Eur.J. Pharm., 157, 13 (1981)t a ligand marked with a radioistope wasreacted with an angiotensin II receptor and the reactant was filteredwith a glass fiber to remove unreacted ligand. After washing the filter,the amount of the remaining isotope was measured to determine thebinding activity of the ligand, as described below in detail.

(i) Isolation of angiotensin II receptor

Sprague-Dawley rats and Wistar rats of 250 to 350 g (from The KoreaResearch Institute of Chemical Technology) were tested and the testprocedures were carried out at 4° C., unless otherwise specified.Adrenal gland was separated from the Sprague-Dawley rats (liver, in thecase of Wistar rats) into cortex and medulla. The separated adrenalcortex and medulla were washed with a sucrose buffer solution (0.2Msucrose, 1 mM EDTA, 10 mM Tris, pH 7.2) and homogenized in the samebuffer solution by using a Teflon pestle and a Brinkmann homogenizer.The homogenates were centrifuged at 3,000× g for 10 minutes to removeprecipitates and further centrifuged at 12,000× g for 13 minutes. Thefinal supernatants were centrifuged at 102,000× g for 1 hour to obtainprecipitates, which were washed with a Tris buffer solution (50 mM Tris,5 mM MgCl₂, pH 7.2) and re-centrifuged at 102,000× g for 1 hour. Theresulting precipitates were immediately processed at the following stepor stored at -70° C.

The precipitates were suspended in a Tris buffer solution. The amount ofprotein was determined by using a Bio-Rad DC protein analyzing kit andthe protein concentration was adjusted to the amounts of: 0.2 to 0.3mg/ml (Sprague-Dawley rat: adrenal cortex), 1.5 to 2.0 mg/ml(Sprague-Dawley rat: adrenal medulla), and 1.5 to 2.0 mg/ml (Wistar rat:liver). To the suspension, bovine serum albumin (BSA) was added to aconcentration of 0.25 wt % and the resultant was immediately processedat the following step or stored at -70° C.

(ii) Measurement of angiotensin II receptor binding capacity

50 μl (based on ligand) of [³ H] angiotensin II (NEN, NET-446) and 10 μlof each of the test compounds with various concentrations were added tothe buffer solution (50 mM Tris (pH 7.2), 5 mM MgCl₂, 0.25% BSA) toadjust the final volume to be 0.5 ml. Losartan (Dup 753), which isdisclosed in EP No. 400,974 issued to Merck, was used as the controlcompound. 100 μl of the receptor suspension was added thereto and theresulting solution was reacted for 60 minutes while stirring in a waterbath at 25° C. 3 ml of cold buffer solution for analysis was added tocease the reaction. The isotope which was bound to the receptor wasisolated from the resultant by using Brandel Cell Harvester System withWhatman glass fiber GF/C. After washing the filter, the radioactivity ofthe filter was determined by using a liquid scintillation counter.Binding inhibition (%) of the test compound was calculated as follows:

    Binding Inhibition (%)=[{(T-B)-(S-B)}/(T-B)]×100

wherein T is the radioactivity (cpm) of the reaction product untreatedwith the test compound, S is the radioactivity (cpm) of the reactionproduct treated with the test compound, and B is the radioactivity (cpm)of blank test.

The results are given in Table 1.

                  TABLE 1                                                         ______________________________________                                                      Binding                                                         Compound      Inhibition (%)                                                  ______________________________________                                         1            91.1                                                             2            95.0                                                             3            96.3                                                             4            71.2                                                             5            64.9                                                             6            91.2                                                             7            79.8                                                             8            68.9                                                             9            30.5                                                            10            91.1                                                            11            99.9                                                            12            63.2                                                            13            90.5                                                            14            92.1                                                            15            88.6                                                            16            62.9                                                            17            50.3                                                            18            57.1                                                            19            88.7                                                            20            89.0                                                            21            86.5                                                            22            90.1                                                            23            93.4                                                            24            76.1                                                            25            87.8                                                            26            94.0                                                            27            81.3                                                            28            78.9                                                            29            83.6                                                            30            90.2                                                            31            97.8                                                            32            98.8                                                            33            73.3                                                            34            95.6                                                            35            97.9                                                            36            75.4                                                            37            92.8                                                            38            95.4                                                            39            87.5                                                            40            90.4                                                            Control       48.0                                                            compound                                                                      (Dup 753)                                                                     ______________________________________                                    

As can be seen from Table 1, the compounds of the present inventioninhibit angiotensin II receptor binding more effectively than thecontrol compound, which implies their antihypertensive activity.

While the invention has been described with respect to the specificembodiments, it should be recognized that various modifications andchanges may be made by those skilled in the art to the invention whichalso fall within the scope of the invention as defined by the appendedclaims.

What is claimed is:
 1. An imidazole compound of formula(I) andpharmacologically acceptable salts thereof: ##STR7## wherein: A is astraight, branched or cyclic C₁ -C₆ alkyl group, or OR₁ wherein R₁ is ahydrogen, or a straight, branched or cyclic C₁ -C₆ alkyl radical;B is ahalogen, CF₃ or CF₂ CF₃ ; X is N or N-oxide; Y is --CH₂ --, --CH(OR₁)--wherein R₁ is the same as defined above, or --C(═O)--; n is 0 or aninteger of 1 to 4; Z is a halogen, --OH, --OR₁, --NR₁ R₂, --N(═O)R₃ R₄,--C(═O)R₁, --C(═O)OR₁, --CH(OR₁)₂ or --C(═O)NR₁ R₂ wherein R₁ is thesame as defined above, R₂ is, independently of R₁, a hydrogen, or astraight, branched or cyclic C₁ -C₆ alkyl radical, and R₃ and R₄ areindependently a straight, branched or cyclic C₁ -C₆ alkyl radical; and Dis a hydrogen, or a straight, branched or cyclic C₁ -C₆ alkyl radical.2. The compound of claim 1 wherein A is a C₃ -C₅ alkyl group; B is Cl; Xis N or N-oxide; Y is --CH(OH)-- or --C(═O)--; n is 0 or 1; z is --OH,--NR₁ R₂, --N(═O)R₃ R₄, --C(═O)R₁ or --CH(OR₁)₂ wherein R₁ and R₂ areindependently a hydrogen or a C₁ -C₃ alkyl radical, and R₃ and R₄ areindependently a C₁ -C₃ alkyl radical; and D is a hydrogen, or astraight, branched or cyclic C₁ -C₄ alkyl radical.
 3. The compound ofclaim 1 which is selected from the group consistingof:{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(dimethoxymethyl)-1-oxypyridin-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-formyl-1-oxypyridin-2-yl)methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-hydroxymethyl-1-oxypyridin-2-yl)methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(dimethoxymethyl)pyridin-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-formylpyridin-2-yl)methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(diethylamino)methyl-1-oxypyridin-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-((diethyl)(oxy)amino)methyl-1-oxypyridin-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-((diethylamino)methyl)pyridin-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-[((diethyl)(oxy)amino)methyl]pyridin-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-bromo-1-oxypyridin-2-yl)methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(1-hydroxyethyl)-1-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-acetyl-1-oxypyridin-2-yl)methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(6-methoxycarbonyl-1-oxypyridin-2-yl)methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)-1-oxypyridin-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(5-formyl-1-oxypyridin-2-yl)methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)pyridin-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(diethylamino)methyl-1-oxypyridin-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-methyl]-3H-imidazo-4-yl}[5-((diethyl)(oxy)amino)methyl-1-oxypyridin-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(5-((diethylamino)methyl)pyridin-2-yl}methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}{5-[((diethyl)(oxy)amino)methyl]pyridin-2-yl}methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo-4-yl}[6-(diethylamino)carbonyl-1-oxypyridin-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[6-(hydroxyimino)methyl-1-oxypyridin-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}[5-(dimethoxymethyl)-6-methyl-1-oxypyridin-2-yl]methanone;{2-butyl-5-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol-4-yl}(5-formyl-6-methyl-1-oxypyridin-2-yl)methanone;and mixtures thereof.
 4. A process for preparing a compound offormula(I) which comprises:(a) reacting a compound of formula(II) withan alkyl lithium to produce a compound of formula(II'); (b) reacting thecompound of formula(II') with a compound of formula(III) to give acompound of formula(IV); (c) oxidizing the compound of formula(IV) togive a compound of formula(V); (d) deprotecting the compound offormula(IV) or (V) to give a compound of formula(VI) or (VII),respectively; and (e) converting the compound of formula(VI) or (VII) toproduce the compound of formula(I) ##STR8## wherein: J is Br, Cl or H;Kis --(CH₂)_(n) CH(OR₁)₂ or --(CH₂)_(n) NR₁ R₂ wherein R₁ and R₂ are thesame as defined in claim 1; P₁ is a tetrazole protecting group; and A,B, D, X and n are the same as defined in claim
 1. 5. A pharmaceuticalcomposition comprising a therapeutically effective amount of theimidazole compound of claim 1 and a pharmaceutically acceptable carrieror adjuvant.